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Originally published as JCO Early Release 10.1200/JCO.2008.16.9870 on June 2 2008 © 2008 American Society of Clinical Oncology.
Imatinib Therapy for Chronic Myeloid Leukemia: Where Do We Go Now?
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX The use of imatinib has greatly improved the outcome of patients with chronic myeloid leukemia (CML). The efficacy of imatinib became apparent in the International Randomized Study of Interferon and STI571 (IRIS).1 One issue with the IRIS study is the number of patients that may have been lost to follow-up. For example, in the most recent update, data is available for only 364 (66%) of the 553 patients treated with imatinib. Because many patients came off study for administrative reasons despite a favorable response once the drug became available after approval from regulatory agencies, the true rates of success and failure are difficult to estimate. In this issue, de Lavallade et al2 present a series of 204 consecutive patients with newly diagnosed CML treated with standard-dose imatinib, nearly all of them outside of the IRIS study. The main value of this study is to provide independent confirmation of the IRIS study results by an intention-to-treat analysis, with follow-up available for all patients. Despite the shorter follow-up (median, 38 months), the results are very similar to those in the IRIS trial. A complete cytogenetic response (CCyR) was achieved in 77% of patients and the projected 5-year event-free survival at 5 years is 81.3%. With these excellent results, one important question is: Can imatinib be improved on? Or, do we even need to try to improve on imatinib? The answer to the second question is easier. Despite the outstanding results obtained so far, there is still room for improvement. de Lavallade et al2 report that 26% of all patients have discontinued imatinib, mostly because of resistance, with only a few discontinuing because of intolerance. Using a broader definition of event-free survival that includes failure to achieve major cytogenetic remission (MCyR) and intolerance to imatinib (in addition to the standard definition that includes loss of compete hematologic response, loss of MCyR, increasing WBC count, death resulting from any cause or progression to accelerated or blast phase), the 5-year probability is 63%. Furthermore, we could consider as an event the inability to achieve or the loss of CCyR. Thus, despite the unquestionable outstanding results with imatinib, there is both room and need for improvement. It is more difficult to answer the question of how we will improve on these results. With imatinib, we have a rate of CCyR of approximately 80% and an overall survival near 90% at 5 years. And we now have excellent second-line therapy for patients who have experienced failure with imatinib, with the second-generation tyrosine kinase inhibitors (TKIs) dasatinib3 and nilotinib4 that have received regulatory approval, and others (bosutinib, INNO-406)5,6 possibly also on their way. Thus, patients that do not respond well or are intolerant to imatinib may still have a favorable long-term outcome with these new therapies. Still, several approaches can be considered for improving the long-term outcome of CML patients. One is to use higher doses of imatinib. Initial reports suggested that this strategy might result in more and faster remissions (CCyR, major molecular response [MMR], and complete molecular response [CMR]) compared with what can be expected with standard dose imatinib.7 Whether these changes result in an improved long-term patient outcome is unknown, but there are randomized trials comparing standard- with high-dose imatinib that may answer this question. A different approach is to use imatinib in combination with other agents. Interferon, cytarabine, and other agents with known clinical activity in CML or that interfere with other pathways important in CML have been found to be synergistic with imatinib. Initial attempts with such combinations were not very successful.8,9 Still, there is interest in pursuing combinations that might help eradicate all evidence of leukemia, including the elusive leukemic stem cell. The success with second-generation TKIs in treating patients who have experienced failure with prior imatinib therapy paired with their in vitro potency and possibly lower propensity to trigger development of mutations has generated interest in their use as initial therapy for patients with early chronic phase CML.10,11 The early results presented to date are very promising, but additional patients and longer follow-up is needed. One could then ask, What would be needed to dethrone imatinib as the standard of care for patients with newly diagnosed CML? Ultimately, we would like to improve survival, but given the excellent survival at 5 years (88% overall; 95% for CML-related deaths), it is unrealistic to expect an improvement in survival in the short term. Improving survival free from transformation is similarly difficult (93% at 6 years). An improvement in event-free survival would be valuable and is a more reachable goal, particularly if we consider a broader definition of event free, as suggested by de Lavallade et al2 that includes toxicity and failure to achieve (or loss of) MCyR or CCyR. In this case, 5-year probability of event-free survival is 62.7%. However, in CML we have the advantage of having excellent surrogate markers (CCyR) for overall and event-free survival. Thus, improving the rate of CCyR would be desirable. The current overall CCyR rate with imatinib is 77% (de Lavallade et al) to 82% (IRIS). High-dose imatinib and the new TKIs have induced responses in more than 90% of patients, and there is indirect evidence that this may lead to an improved event-free and transformation-free survival.12 Improving the rate of molecular responses can be pursued; there are data to suggest that patients with MMR have an improved event-free survival and survival free from transformation compared with those with CCyR but no MMR.13 However, the difference is small. In the IRIS study, the event-free survival at 60 months is 97% for patients with MMR and 89% for those with CCyR but nor MMR; the corresponding figures for transformation-free survival are approximately 100% and 95%. Furthermore, in the study by de Lavallade et al,2 there is no difference in progression-free or overall survival for patients with CCyR, with or without MMR. Corresponding figures for survival without transformation by CCyR, with or without MMR by 18 months, are 100% and 98%, respectively. Achieving CMR could be considered the optimal goal. It has been suggested in some selected populations that achieving CMR is associated with more durable responses.14,15 However, given that the difference in transformation-free and event-free survival between MMR and no MMR (for patients with CCyR) is small, it is likely that the overall impact of CMR is also small. Achieving an early response (CCyR, MMR) has been associated with the best outcome, and although patients with later responses (eg, CCyR) may have also excellent outcome, patients not achieving an early response face the competing probabilities of improving their response compared with progressing. Thus, improving the rate of patients who achieve early optimal response would be desirable, although it is unclear whether, for those patients that are induced into an early response (for example, with high-dose imatinib or second-generation TKIs) this improved their long-term outcome or whether these responses might be transient, "cosmetic" responses. The early evidence from the studies with high-dose imatinib where responses occur rapidly in most patients suggests that the outcome is indeed improved compared with historical results with standard-dose therapy. Randomized studies will have to confirm this observation. We do still have needs in the treatment of CML. One important goal of therapy would be to eliminate the leukemic stem cell. This has been interpreted as the requirement for achieving cure. However, we do not now have adequate means of identifying and quantifying this stem cell during the course of therapy. Still, from preclinical studies it appears that none of the existing therapies (imatinib, dasatinib, nilotinib, or other TKIs) are able to achieve this goal. At the practical level, a strategy that could allow patients to eventually discontinue all therapy with enough confidence that the disease would not recur would be highly desirable. Except for roughly 50% of patients previously treated with interferon16 and anecdotal instances without prior interferon therapy, treatment discontinuation has resulted in relapse, despite patients’ having achieved a prior CMR. Even with prior interferon therapy, a 50% probability of relapse should be considered unacceptable. Significantly more research has to be devoted to better understanding the nature of the leukemia stem cell and how to eliminate it, to identify biologic features that identify patients who might be destined to have an optimal response and long-term outcome, and to counteract those factors associated with inferior outcome. The excellent results achieved to date with imatinib should not be translated into complaisance with the outcome. This is not time to slow down our efforts to better understand the disease and improve its therapy. The deeper we go in our understanding of the biology and therapy of CML, the more we find yet to be discovered. We should have more, and ideally all, patients included in clinical trials, and more basic and translational research if we are to accomplish the ultimate goal: to cure CML in all patients. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Jorge E. Cortes, Novartis, BMS, Wyeth Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on June 2, 2008. REFERENCES
1. Druker BJ, Guilhot F, O'Brien SG, et al: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408-2417, 2006 2. de Lavallade H, Apperley JF, Khorashad JS, et al: Imatinib for newly diagnosed patients with chronic myeloid leukemia: Incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 26:3358-3363, 2008 3. Hochhaus A, Kantarjian HM, Baccarani M, et al: Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109:2303-2309, 2007 4. Kantarjian HM, Giles F, Gattermann N, et al: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110:3540-3546, 2007 5. Cortes J, Bruemmendorf T, Kantarjian H, et al: Efficacy and safety of bosutinib (SKI-606) among patients with chronic phase Ph+ chronic myelogenous leukemia (CML). Blood 110, 2007 (abstr 733) 6. Kantarjian H, Cortes J, Le Coutre P, et al: A phase I study of INNO-406 in patients with advanced Philadelphia (Ph+) chromosome-positive leukemias who are resistant or intolerant to imatinib and second generation tyrosine kinase inhibitors. Blood 110, 2007 (abstr 469) 7. Kantarjian H, Talpaz M, O'Brien S, et al: High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 103:2873-2878, 2004 8. Baccarani M, Martinelli G, Rosti G, et al: Imatinib and pegylated human recombinant interferon-alpha2b in early chronic-phase chronic myeloid leukemia. Blood 104:4245-4251, 2004 9. Gardembas M, Rousselot P, Tulliez M, et al: Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood 102:4298-4305, 2003 10. Cortes J, O'Brien S, Jones D, et al: Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). Blood 110, 2007 (abstr 30) 11. Cortes J, O'Brien S, Jabbour E, et al: Efficacy of nilotinib (AMN107) in patients (Pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). Blood 110, 2007 (abstr 29) 12. Aoki E, Kantarjian H, O'Brien S, et al: High-dose imatinib mesylate treatment in patients with untreated early chronic phase chronic myeloid leukemia. J Clin Oncol 24:345s, 2006 (abstr 6535)[CrossRef] 13. Hughes TP: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423-1432, 2003 14. Press RD, Galderisi C, Yang R, et al: A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res 13:6136-6143, 2007 15. Branford S, Seymour JF, Grigg A, et al: BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res 13:7080-7085, 2007 16. Rousselot P, Huguet F, Rea D, et al: Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 109:58-60, 2007 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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